Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy

Abstract

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.

Key points

  • Lupus nephritis (LN) is a heterogeneous complication of systemic lupus erythematosus that remains a considerable unmet medical need.

  • Genetic and epigenetic factors confer risks of LN incidence and progression.

  • Single-cell analyses and enhanced microscopic analyses of renal tissues are yielding new information about LN pathogenesis and the progression of chronic kidney disease.

  • Improvements in risk assessment using genetic or transcriptomic biomarkers could enable the design of clinical trials to prevent LN onset and progression.

  • Trials might need to be tailored according to the genetic profile of the patient, a biomarker-based evaluation of their renal tissue and/or the mechanism of action of each new drug.

  • Developments in the understanding of tubulointerstitial injury and repair are yielding new strategies for preserving renal function and preventing fibrosis.

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Fig. 1: Glomerular injury and tubulointerstitial damage in lupus nephritis.
Fig. 2: Data integration for lupus nephritis diagnosis and therapy.

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Acknowledgements

The work of the authors was funded by The Lupus Research Alliance, the US National Institutes of Health (grant RO1 AR064811–01 to A.D.) and the US Department of Defense (grant W81XWH-17–1–0657 to A.D.).

Review criteria

References were selected using Medline search and the terms ‘lupus’ and/or ‘nephritis’ with ‘therapies’, ‘inflammation’, ‘endothelial cells’, ‘podocytes’, ‘biomarkers’, ‘macrophages’, ‘dendritic cells’, ‘T cells’, ‘B cells’, ‘cytokines’, ‘fibrosis’ and ‘renal tubules’. Articles published between 2016 and 2019 were given preference for inclusion. In addition, a personal collection of articles was used that includes ~5,000 references related to SLE and novel therapies.

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Nature Reviews Rheumatology thanks G. Gilkeson, R. Misra and F. Yu for their contribution to the peer review of this work.

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Glossary

Capillary rarefaction

A loss of capillary structure leading to reduced density of microvascular networks.

Glomerular crescents

A response to severe injury in which crescent-shaped glomerular lesions that consist of epithelial cells, fibroblasts, immune cells and matrix form adjacent to the Bowman’s capsule.

Foot process effacement

A podocyte reaction to injury or damage in which the epithelial foot processes become flattened and lose their barrier function, resulting in proteinuria.

Glomerular tuft

A network of small blood vessels and supporting cells that forms the initial structural component of the nephron.

Glomerulosclerosis

Scarring of the glomeruli that leads to loss of function.

Fate mapping

A technique used in developmental biology to study the embryonic origin of adult cells, tissues and structures.

Exhaustion signature

A cell state or phenotype with progressive loss of effector cytokine or cytotoxic function owing to prolonged antigen stimulation, often characterized by the increased expression of immune checkpoint inhibitory receptors, alterations in metabolic function and a distinct transcriptional profile that differs from that of anergic cells.

Polypharmacy

The use of multiple medications to treat complex medical conditions.

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Maria, N.I., Davidson, A. Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy. Nat Rev Rheumatol 16, 255–267 (2020). https://doi.org/10.1038/s41584-020-0401-9

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